title: Mutations in G protein-coupled receptors that impact receptor trafficking and reproductive function.
abstract: G protein coupled receptors (GPCRs) are a large superfamily of integral cell surface plasma membrane proteins that play key roles in transducing extracellular signals, including sensory stimuli, hormones, neurotransmitters, or paracrine factors into the intracellular environment through the activation of one or more heterotrimeric G proteins. Structural alterations provoked by mutations or variations in the genes coding for GPCRs may lead to misfolding, altered plasma membrane expression of the receptor protein and frequently to disease. A number of GPCRs regulate reproductive function at different levels; these receptors include the gonadotropin-releasing hormone receptor (GnRHR) and the gonadotropin receptors (follicle-stimulating hormone receptor and luteinizing hormone receptor), which regulate the function of the pituitary-gonadal axis. Loss-of-function mutations in these receptors may lead to hypogonadotropic or hypergonadotropic hypogonadism, which encompass a broad spectrum of clinical phenotypes. In this review we describe mutations that provoke misfolding and failure of these receptors to traffick from the endoplasmic reticulum to the plasma membrane. We also discuss some aspects related to the therapeutic potential of some target-specific drugs that selectively bind to and rescue function of misfolded mutant GnRHR and gonadotropin receptors, and that represent potentially valuable strategies to treat diseases caused by inactivating mutations of these receptors.
authors.affiliation: Division of Reproductive Health, Research Center in Population Health, National Institute of Public Health, Cuernavaca, Mexico; Divisions of Reproductive Sciences and Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006, USA. Electronic address: aulloaa@unam.mx.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Ulloa-Aguirre
authors.affiliation: Research Unit in Reproductive Medicine, UMAE Hospital de Ginecobstetricia "Luis Castelazo Ayala", Mexico, DF, Mexico.
authors.forename: Teresa
authors.initials: T
authors.lastname: Zariñán
authors.affiliation: Department of Biomedical Sciences, School of Public Health, University at Albany, Albany, NY, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Dias
authors.affiliation: Divisions of Reproductive Sciences and Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006, USA; Department of Pharmacology and Physiology, Oregon Health and Science University, Beaverton, OR 97006, USA; Department of Cell and Developmental Biology, Oregon Health and Science University, Beaverton, OR 97006, USA; Department of Obstetrics and Gynecology, Oregon Health and Science University, Beaverton, OR 97006, USA.
authors.forename: P Michael
authors.initials: PM
authors.lastname: Conn
mesh_terms: D000818:Animals; D006801:Humans; D007006:Hypogonadism / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D021381:Protein Transport; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D012098:Reproduction / Q000502:physiology*
chemical_list: D043562:Receptors, G-Protein-Coupled
keywords: G protein-coupled receptors; Gonadotropin receptors; Gonadotropin-releasing hormone receptor; Hipogonadism; Intracellular trafficking; Pharmacological chaperones